BEFORE THECOMMITTEE ON GOVERNMENT REFORM
U.S. HOUSE OF REPRESENTATIVES

DECEMBER 5, 2000

Introduction

Mr. Chairman and Members of the Committee, I am Jonca Bull,
M.D., Deputy Director of the Office of Drug Evaluation V,
Center for Drug Evaluation and Research (CDER), Food and Drug
Administration (FDA or the Agency). I appreciate the opportunity
to discuss the Committee’s concerns regarding the drug Accutane.
Helping to ensure the safe and effective use of Accutane has
involved difficult scientific and ethical issues for FDA.
We have taken our regulatory responsibilities concerning this
drug very seriously.

FDA approved Accutane in 1982 for use in the treatment of
severe, recalcitrant cystic acne that is unresponsive to conventional
therapy, including antibiotics. In most cases, cystic acne
is severely disfiguring, causing red cysts and nodules, which
can leave deep scars. Accutane is uniquely effective in treating
patients with this disease, but is associated with serious
adverse events including birth defects. For this reason, it
continues to be one of FDA’s most difficult challenges in
the area of post-approval risk management.

FDA must constantly balance the public need for access to
effective therapies against the risks associated with their
use. FDA has been proactive in addressing the issue of risk
management. For example, as one of her first initiatives as
Commissioner, Dr. Jane E. Henney established a Task Force
to evaluate the system for managing risks of FDA-approved
medical products, focusing particularly on FDA’s part in the
system. We recognize that FDA is but one of many players that
can and must have an impact on the safety of health care in
the United States.

One of FDA’s primary responsibilities is in the premarket
phase. A major goal of the premarketing review of a drug is
to help ensure by the careful review of the data collected
in the clinical trials that products are truthfully and adequately
labeled for their intended use and target population. Approval
of a drug product is based on FDA’s acceptance and review
of data collected during the course of the drug’s development,
including the results of clinical trials demonstrating that
the drug is safe and effective for its intended use. No drug,
however, is 100 percent safe; no pharmacologically active
medicine exists that does not have side effects. FDA realizes
that when an approved new drug becomes widely used in clinical
practice, health care professionals may observe differences
from clinical trial results in both the incidence and/or types
of adverse drug experiences. For this reason, FDA's other
primary responsibility is postmarketing surveillance--to monitor
rare, serious, unexpected adverse drug events (i.e., serious
or unexpected adverse reactions not described in the approved
labeling). The Agency monitors reports from manufacturers,
consumers, and health professionals to determine if any safety
problems or trends can be identified and takes action accordingly.

After a drug is approved, the prescriber assumes primary
responsibility for managing the product risks (and benefits)
for the individual patient because of his/her specific knowledge
of the unique circumstances surrounding each individual patient.
In this situation, FDA’s role has been to assist the prescriber
by requiring that risks and benefits are described in the
labeling and promotional materials, and to assure, through
postmarketing surveillance of reports of potential new safety
information, that this new information about risks is relayed
promptly to clinicians. To minimize risks, product labeling
often describes how to select patients, how to select and
modify the dose schedule for individual patients, how to avoid
interacting treatments, how to monitor for drug toxicity,
and what measures to use to avoid or mitigate drug toxicity.
FDA and manufacturers rely on practitioners to prescribe products
with full knowledge of the prescribing information and limitations
detailed in the product labeling. Likewise, practitioners
presume their patients will use their medications according
to directions given. We know, however, that this does not
always happen.

Because all drugs have risks, it is critical that patients
are fully informed about potential side effects as well as
benefits before deciding to take a particular medicine. Once
the choice to take a product is made, patients need to understand
how to take the medicine properly, the precautions they should
observe, and the signs of possible side effects. FDA has worked
for over two decades to help ensure that patients get the
full information that they need to take medicines as safely
as possible. In 1980, the Agency published a rule requiring
FDA approved patient labeling for ten drugs/drug classes,
with the expectation that this would be extended to all prescription
drugs. In 1982, the rule was revoked in favor of private sector
efforts to provide patient information that FDA would monitor.

By 1994, FDA surveys showed that only 58 percent of patients
were receiving some sort of information with prescriptions.
Therefore, in 1995, FDA published a proposed rule, commonly
called MedGuide, that set forth goals for the distribution
of useful prescription drug information to consumers, and
would have required manufacturers to include drug information
for the patient when a product posed a serious and significant
public health concern. In August 1996, Congress passed legislation
that provided another opportunity for private achievement
of the MedGuide goals. Consequently, a private sector Action
Plan was developed to meet the need. In 1998, FDA published
a final rule requiring patient labeling (MedGuides) for products
that pose "serious and significant" public health
concerns, anticipating an average of no more than five to
ten products annually. This rule became effective on June
1, 1999, and provides the framework under which the proposed
Accutane MedGuide is being developed. For the vast majority
of products that will not have MedGuides, patient information
given out with prescriptions is expected to be provided by
the voluntary private sector effort.

Adverse Effects Associated with Accutane

When Accutane was approved, the most common adverse reaction
reported was severe drying and chapping of the lips, which
occurred in about 90 percent of patients. In addition, 25
percent of patients treated had an elevation of serum triglycerides
(fatty substances in the blood), and elevated cholesterol
levels. The labeling of the drug, therefore, suggested that
physicians closely monitor these levels during treatment.
Also, the approved labeling also informed physicians that
about 40 percent of patients developed conjunctivitis, 16
percent developed musculoskeletal symptoms, less than 10 percent
of patients experienced rash or thinning of hair, and about
five percent experienced peeling of palms and soles, skin
infections, nonspecific urogenital findings, nonspecific gastrointestinal
symptoms, fatigue, and increased susceptibility to sunburn.
Because teratogenicity was observed in animals, Accutane was
contraindicated in patients who were pregnant or planning
to become pregnant, or in nursing mothers.

During the first ten years after the initial marketing of
Accutane, the primary focus of concern was managing the established
risk of birth defects, a risk initially suspected and noted
in the labeling. FDA’s staff held numerous meetings with the
company, analyzed adverse event reports, and convened at least
seven Advisory Committee meetings.

Because Accutane is the only currently available product
that can potentially cure cystic acne, FDA permitted the continued
marketing of the product in spite of the known risk of birth
defects and other serious reactions. FDA has proceeded to
periodically reassess the risk/benefit equation. From 1983
through 1988, FDA and the company stepped up efforts to communicate
the significant risks to women of child-bearing age. These
efforts included:
1) physician labeling changes; 2) repeated mailings of special
letters to doctors and pharmacists detailing proper use and
emphasizing the risks; 3) two articles in FDA’s Drug Bulletin,
which reached more than a million health professionals, emphasizing
proper prescribing of Accutane; 4) distribution to patients
through doctors of a patient information leaflet highlighting
the risks; 5) distribution to pharmacists of red warning stickers
to be placed on each prescription bottle; and 6) issuance
of press releases and background papers to the general news
media for use in warning the public about the risks associated
with Accutane.

Despite these efforts, there was evidence that the drug was
being used in thousands of women of child-bearing age with
less severe acne than that for which the drug was approved,
i.e., for severe recalcitrant cystic acne which does not respond
to conventional therapy. In 1988, the Centers for Disease
Control and Prevention (CDC) published an article describing
four cases of multiple, serious birth defects occurring from
1983 to 1987, and cited additional cases previously reported.
Consequently, FDA convened another Dermatologic Drugs Advisory
Committee (the Committee) meeting to consider various options
for dealing with the problem. The Committee listened to presentations
from experts in several medical specialties, as well as scientists
from CDC, FDA, Hoffman La-Roche, Public Citizen’s Health Research
Group, the American Academy of Pediatrics, and the American
Academy of Dermatology. At FDA’s request, additional experts
participated in the deliberations, including doctors specializing
in obstetrics, birth defects, genetic diseases, reproductive
sciences, clinical pharmacology, and epidemiology.

At the end of the day-long session, the Committee unanimously
recommended continued sale of Accutane with revised labeling
for physicians and patients and further restrictions in connection
with distribution of the drug including: 1) increased prominence
and strength of warnings and contraindications through new
packaging, and more explicit information about the degree
of risk; 2) recommended use only in women who have had a negative
pregnancy test (if they are able to bear children); and 3)
written acknowledgement from patients taking the drug that
they have been informed of the risk of birth defects. In a
split vote, the Committee recommended that the drug’s use
be restricted by one or more of the following: 1) dispensing
only by certain physicians, 2) special restrictions for high
risk patients, 3) requiring a second opinion for high risk
female patients, or 4) requiring an educational program for
certification of physicians to dispense the drug. The Committee
also asked for continued monitoring of use and reports of
all adverse events.

After the Committee made its recommendations, in May 1988,
FDA issued a letter to Hoffman-La Roche outlining actions
designed to limit or prevent misuse of the drug. The May l988
letter provided in part: 1) that Accutane be dispensed in
a blister pack with the patient warnings (including pictures
showing the severity of birth defects) and other information
as part of the package itself (this information was provided
in addition to the pamphlets physicians provide to patients);
and 2) physicians and women patients be asked to sign a form
acknowledging their understanding of the very great likelihood
of serious birth defects if the drug was taken during pregnancy.
More detailed physician and patient labeling was also mandated.
FDA’s letter also called for extensive educational campaigns
aimed at physicians, pharmacists, and patients and encouraged
publication of advertisements on the teratogenic effects of
the drug.

Furthermore, FDA’s 1988 letter stated that the blister pack
should include a tear-off postcard addressed to the company
requesting the patient’s name, telephone number, address,
and permission to be contacted by the company for studies
requested by FDA. FDA requested a follow-up study to ascertain
patient awareness, disease status, contraception use, information
regarding any pregnancy, and the outcome of that pregnancy.
The letter also requested reporting of all pregnancy exposures
and an effort to find out why patients, despite warnings,
became pregnant or used the drug when already pregnant. The
company was asked to do further clinical trials using lower
doses of the drug, or higher doses for a shorter period of
time.

In mid-1989, the company fully implemented its "Pregnancy
Prevention Program for Women on Accutane." This program
included the unprecedented educational efforts and restrictions
requested by the May 1988 letter from FDA. Consequently, in
May 1990, Accutane underwent review by FDA’s Dermatologic
Drugs Advisory Committee. FDA asked the Committee to evaluate
the effectiveness of the company’s efforts to curb drug/pregnancy
exposures and birth defects, and whether additional measures
were necessary. The Committee concluded that the manufacturer
made a very strong effort to inform patients and physicians
of the risk associated with Accutane but that the data on
recent efforts was limited. Data included one infant reported
with defect in 1990, four in 1989, and three in 1988, compared
to ten for 1987 and 12 for 1986. The Committee recommended:
1) that educational materials emphasize the importance of
the initial pregnancy test before beginning treatment with
Accutane; 2) that physicians stress to patients the importance
of the informed consent forms and that such forms be available
in numerous languages; 3) pregnancy prevention counseling
be made available and emphasized; and 4) that the manufacturer
design a program to ensure that patients returned all leftover
medications so they would not take Accutane without a dermatologist’s
supervision.

Warnings Regarding Accutane and Depression and Suicidal
Behavior

The original New Drug Application (NDA) safety database for
Accutane did not contain reports of depression or mood disorders.
In the mid-1980s, however, due to postmarketing reports of
depression, a labeling revision was done to include depression
as part of the adverse reactions section. The labeling provided:
"Depression has been reported in some patients on Accutane
therapy. In some of these patients, this has subsided with
discontinuation of therapy, and recurred with reinstitution
of therapy." In addition, the adverse reactions section
stated: "The following CNS reactions have been reported
and may bear no relationship to therapy: seizures, emotional
instability, dizziness, nervousness, drowsiness, malaise,
weakness, insomnia, lethargy, and paresthesias."

FDA began a re-evaluation of the psychiatric illness reports
in 1996, when a physician in the reviewing division noted
two cases of suicide in a routine listing of recent adverse
events associated with Accutane. Reports such as this do not
necessarily mean that the event has any relationship to the
drug. Accutane, however, had previously been associated with
depression as already noted in the Accutane labeling. Because
suicide is the most serious consequence of depression, the
FDA reviewing division enlisted the help of specialists in
the FDA epidemiology division to try to determine whether
the cases could possibly be related to Accutane use. The division
undertook a systematic analysis of the published literature,
previously reported cases entered into databases, and incoming
safety reports.

These reports were not numerous relative to the rate of depression
and suicide expected to be seen in the population likely to
receive Accutane, namely teens and young adults (sometimes
referred to as the "background" rate). Some of the
reports, however, included important details that did suggest
the possible involvement of Accutane. Some reports described
a consistent pattern of symptoms in patients with no previous
history of such symptoms and no other identifiable reason
for their occurrence. Other cases were described in which
the symptoms began during the Accutane treatment and then
resolved soon after the medicine was stopped. In a subset
of these cases, Accutane was then restarted and the same symptoms
returned. While these findings do not prove that Accutane
causes psychiatric illness, they are suggestive of a possible
link.

In May 1997, when an association appeared possible, FDA began
working with the company to fully evaluate the data and determine
appropriate next steps. In February 1998, a labeling change
included psychiatric adverse events in the professional labeling’s
Warnings section, stating: "Psychiatric Disorders: Accutane
may cause depression, psychosis, and rarely, suicidal ideation,
suicide attempts, and suicide. Discontinuation of Accutane
therapy may be insufficient; further evaluation may be necessary.
No mechanism of action has been established for these events
(see Adverse Reactions: Psychiatric)." The Adverse Reactions
section stated "psychiatric: suicidal ideation, suicide
attempts, suicide, depression, psychosis (see warnings: Psychiatric
Disorders), emotional instability." While Accutane labeling
had previously included depression in the adverse reactions
section, it was believed that the addition of wording that
called attention to possible suicidal behavior would help
to ensure that prescribers would take appropriate actions
if patients developed mood changes. Even though a causal relationship
between Accutane and suicidal behavior still had not been
scientifically established, this action was thought prudent
given the available information.

In addition, a letter was sent to doctors who might prescribe
Accutane, as well as those likely to see patients who develop
psychiatric disturbance. FDA also posted a special notice
about Accutane on its public website and released a Talk Paper
to the press to help ensure wide attention and dissemination
of this warning. FDA also instructed the company to discontinue
promotional claims regarding the psychosocial benefits of
Accutane treatment for acne.

Patient information is intended to remind patients about
important things they discussed about their treatment with
their prescriber. It is often not identical to the wording
of professional labeling. Prior to the 1998 change in the
professional labeling, there were five "signs" of
potentially serious problems listed as bullets for patients,
with all capital letter instructions to stop Accutane and
call their doctor immediately. All of these "bullets"
except mood changes reflected serious adverse events in the
Warning section of the professional labeling. Thus, when psychiatric
problems were upgraded in 1998 to the Warning section of the
professional labeling, it was already in the proper list in
the patient information. As with other "symptoms"
of possible serious or fatal problems, the patient information
on mood changes did not include specific information about
the possible outcome (suicide), instead being followed by
the advice to stop the drug and call the doctor immediately
due to the possibility of serious consequences. For example,
the patient information said to watch out for yellow skin
or abdominal pain. This reflects professional labeling about
hepatotoxicity or pancreatitis, which can be fatal.

After the 1998 change regarding psychiatric disorders, FDA
embarked on a very comprehensive re-assessment of the overall
labeling and risk management for Accutane. This comprehensive
re-evaluation included the following: 1) ways to improve methods
to prevent birth defects; 2) possible interactions with drugs
not on the market in 1982 when Accutane was approved (e.g.,
new contraceptive therapies); 3) epidemiologic study of accumulating
reports of adverse events not in the labeling to decide on
inclusion; 4) safety issues specific to young growing patients;
5) re-organization of the information to make it more useable
for prescribers; and 6) re-design of the patient information
to improve visibility of items not related to pregnancy prevention,
adding new information, and providing specific information
about possible outcomes for serious events. The revised patient
information resulting from this work was implemented on an
interim basis with a commitment by the manufacturer to conduct
patient comprehension testing and to pursue further revisions.
The interim revision, implemented in the summer of 2000 captures
the possible outcome for mood disorder (suicide) but did not
accomplish this goal for all of the bulleted serious adverse
events.

FDA and the company also began to address the need for further
research into the potential link between Accutane and psychiatric
events soon after the 1998 labeling change. Roche began a
number of studies. The company and FDA had frequent working
meetings and some results were submitted to FDA beginning
in late 1999. Some of these studies were discussed at the
September 2000 meeting of FDA’s Dermatologic and Ophthalmic
Drugs Advisory Committee, at least one has been published,
and the results of another are expected soon. To date, these
studies do not provide a definitive answer. It is very likely
that a controlled masked clinical study would not be feasible
for ethical and technical reasons and a major goal of seeking
outside expert advice in September 2000 was to explore other
approaches.

September 2000

As noted previously, in September 2000, the Dermatologic
and Ophthalmic Drugs Advisory Committee again discussed Accutane.
The two major topics were prevention of fetal exposures and
risk management strategies for the uncertain risk of psychiatric
effects associated with the use of Accutane. On the pregnancy
prevention issue, the Committee agreed on the following three
goals or principles: 1) no one should begin Accutane therapy
if pregnant; 2) no pregnancies should occur while on Accutane
therapy; and 3) a monitoring program should be implemented
to assess progress toward these goals. FDA presented five
designs to achieve these goals, and the majority of the Committee
voted on a design that included: 1) education and informed
consent; 2) complete participation including registration
of patients and physicians; and 3) tracking of pregnancy exposures
including a pregnancy registry, surveys, and external data.
The Committee did not want restricted distribution.

On the issue of psychiatric events, the Committee unanimously
agreed that there was sufficient concern about Accutane to
justify exploring additional risk management strategies even
though the risk was uncertain. The Committee recommended that
the manufacturer: 1) add the information about the adverse
events to the informed consent document signed by patients
and/or their parents or guardians prior to receipt of Accutane;
2) develop and distribute an enhanced prescriber educational
program about the psychiatric events; and 3) develop and distribute
a Medication Guide for Accutane. The Committee also was asked
whether further studies to help clarify the relationship between
Accutane use and psychiatric events were needed and if so,
what kind of studies. The Committee discussed the many ethical
and technical problems with a controlled clinical trial and
offered ideas for other types of studies with an emphasis
on basic science research, particularly focused on the adolescent
central nervous system, as well as epidemiologic studies in
addition to those already underway. The Agency is working
with the manufacturer to implement the Committee’s recommendations.

Conclusion

Accutane continues to be one of the more challenging products
FDA regulates. We think the record demonstrates the Agency’s
continued concern regarding this product and our efforts to
manage the associated risks. We hope that the future will
bring a product effective for severe recalcitrant cystic acne
without the risk of birth defects or other possible serious
adverse events. We are also hopeful that research will establish
whether or not the psychiatric events associated with the
use of Accutane are truly caused by the drug. We will continue
to work with the manufacturer to keep health professionals
and consumers aware of the risks associated with Accutane
and the circumstances under which it should be used and prescribed.
Thank you for the opportunity to discuss this important matter.